BMPs signaling pathway

Binding of a BMP dimer to its type II receptor recruits type I receptors, so that a heterotetramer is formed with two receptors of each type.

The proximity of the receptors allows the type II receptor to phosphorylate the type I receptor.

One of two identified downstream pathways, the Smad cascade, is initiated by phosphorylation of certain Smad proteins by type I receptors, and the other pathway involves two mitogen-activated protein kinase (MAPK) cascades.

In either case, the consequence is regulation of gene transcription.

The constitutively active kinase domains of type II receptors phosphorylate type I receptors, and this in turn activates the SMAD signaling pathway through phosphorylation of receptor SMADs (SMAD1, SMAD5 and SMAD8).

These associate with co-SMADs (SMAD4) to form a heteromeric complex that translocates to the nucleus and stimulates the expression of a wide range of target genes, including the gene encoding the iron regulatory peptide hepcidin.

Many of the previously known inhibitors of BMP signaling (such as noggin and chordin) act upstream to sequester BMPs and cannot differentiate SMAD-dependent from SMAD-independent signaling.

The activation of the hepcidin gene by IL-6 requires both the JAK-STAT and BMP-SMAD pathways, but how the pathways interact is unclear.

Similarly, TfR2 and the HFE–TfR1 complex can alter hepcidin expression, but it is not known whether their functions require the BMP-SMAD system.

Functions

BMP signaling is implicated in tumor suppression, bone homeostatsis, angiogenesis and metastasis. There are numerous other signaling pathways such as the Ras-MEK pathway that could also modulate the end effects by establishing cross talk among different pathway members.

Disabled Smad signaling in cancer has become increasingly recognized as an important step that affects processes such as loss of growth inhibition, promotion of angiogenesis and metastasis and the epithelial mesenchymal transition.

Although frequent alterations in SMAD4 have been primarily reported in pancreatic and gastrointestinal cancers, the nature of defects involving the Smad signaling pathyways has been elusive in other cancers potentially due to alternate mechanisms and/or targets which become inactivated in the signaling pathway.

Recently, we have developed a novel technique known as Targeted Expressed Gene Display (TEGD). TEGD allows for the identification of related members of a large family of genes, as well as their variants and also enables the determination of their patterns of expression in tissues and tumors.

Furthermore, we extended the practical application of this technique in cancer diagnosis by analyzing the SMAD genes in cancer. We were able to carryout simultaneous evaluation of the existence as well as the levels of expression of the various Smad family members and their variants in cancers.

These analyses were instrumental in providing the first clues that the loss of SMAD8 expression is assoiciated with mulitple types of cancers including 31% of both breast and colon cancers.

The loss of Smad8 expression via epigenetic silencing in a third of breast and colon cancers makes it a significant novel tumor marker with implications for detection, prognosis and therapy of these major cancers.

Smad signaling downstream of the BMPs involving Smad8 could be an important pathway in metastasis/bone metastasis in cancer.